Abstract
INTRODUCTION: Despite multimodality treatment, patients with malignant gliomas only achieve a median survival of 18 months. Our group has pioneered an adoptive T cell immunotherapy that utilizes total tumor RNA-pulsed dendritic cells to expand polyclonal tumor-reactive T cells ex-vivo. The strongest anti-tumor efficacy of adoptive T cell immunotherapy is achieved when combined with syngeneic hematopoietic stem and progenitor cell (HSPC) transplant. The inclusion of HSPCs leads to a doubling of median survival and 40% long-term cures in treatment-resistant murine malignant glioma, brainstem glioma, and medulloblastoma. In this study, we evaluated the HYPOTHESIS that adoptive T cell immunotherapy drives the differentiation of HSPCs into dendritic cells within the brain tumor microenvironment. METHODS: We evaluated HSPC differentiation and function in the context of immunotherapy in tumor-bearing animals and HSPC proliferation and differentiation in-vitro using a T cell co-culture system. RESULTS: The differentiation of HSPCs into CD11c(+)MHCII(+)CD86(+) dendritic cells in the tumor microenvironment depended on tumor-reactive T cell-released IFN-γ. Additionally, HPSC-derived dendritic cells cross-presented tumor-derived antigens to tumor-reactive T cells, increasing T cell activation within the tumor. When evaluating the impact of HSPCs on host intratumoral immunity, we determined that HSPC transfer strongly supplants host myeloid-derived suppressor cells and downregulates suppressive genes. CONCLUSIONS: We have made novel observations that HSPCs significantly enhance immunotherapy by supplanting host immunity and synergizing with T cells in the tumor microenvironment. A phase I trial evaluating the impact of HSPC transfer on adoptive immunotherapy in pediatric high-grade gliomas is on schedule to open this year (ACTION– FDA IND#BB-17298).